MRI (Magnetic Resonance Imaging) is an imaging technique based on the phenomenon of nuclear magnetic resonance. Functional magnetic resonance imaging (fMRI) is a variation of magnetic resonance imaging which can be used for analysis and evaluation of brain function. Brain function consumes a large amount of energy and this is provided almost exclusively by glucose oxidation. Brain function is therefore dependent on glucose and oxygen, which is provided by the circulating blood. These characteristics have been exploited to study brain function in vivo.
The technique of functional MRI (fMRI) is based on the physiological principle that when nerve cells are active they consume oxygen carried by haemoglobin in red blood cells. In response the small blood vessels in the region dilate and blood flow is increased to the regions of increased neural activity. This delivers a large amount of oxygenated blood to the region.
The oxygen carried by the blood is bound to the protein haemoglobin. The magnetic properties of haemoglobin, oxygenated haemoglobin (oxyhaemoglobin) and deoxygenated haemoglobin (deoxyhaemoglobin) were demonstrated as long ago as 1936. The magnetic resonance (MR) signal of blood is modulated by the ratio of oxyhaemoglobin and deoxyhaemoglobin. Many decades later this property was shown in vivo and was termed “Blood Oxygen Level Dependent” (BOLD) contrast. In BOLD fMRI changes in blood oxygen level are observed as signal changes from a baseline.
In the BOLD method the fact that oxyhaemoglobin and deoxyhaemoglobin are magnetically different is exploited. Oxyhaemoglobin is diamagnetic whereas deoxyhaemoglobin is paramagnetic. As deoxyhaemoglobin is paramagnetic, it alters the T2* weighted magnetic resonance image signal. Thus, deoxyhaemoglobin is sometimes referred to as an endogenous contrast enhancing agent, and serves as the source of the signal for fMRI. The fMRI technique has been widely used for more than a decade to understand brain function by activating different brain areas by appropriate stimuli using different paradigms.
Upon neural activity, oxygen consumption is increased. This results in a corresponding reduction in deoxyhaemoglobin as the increase in blood flow brings more oxyhaemoglobin into the area without an increase of similar magnitude in oxygen consumption. This causes a small change in the magnetic field, and thus the MRI signal, in the active region. As deoxyhaemoglobin is paramagnetic, and the water molecules around the red blood cells are affected by the resulting local magnetic field distortions, a reduction of the T2* magnetic resonance image signal value is observed. Despite the existence of such valuable imaging methods, there remains a need for improved techniques to permit better understanding of physiology, particularly to recognize metabolic dysfunction before it is too late for an appropriate intervention or procedure to be applied.
The concept of the ischaemic penumbra is now more than 30 years old. Following occlusion of a brain artery some of the brain tissues supplied by the vessel perish due to hypoxia/anoxia. This happens due to the inability of cells to produce ATP (energy) leading to cell dysfunction and then cell death. However, some tissues have a capability to recover with appropriate treatment. Astrup (Astrup et al., 1981) first defined ischemic penumbra in 1981 as perfused brain tissue at a level within the thresholds of functional impairment and morphological integrity, which has the capacity to recover if perfusion is improved. Therefore any technique demonstrative of active metabolism within the affected tissues would, at least in theory, also be able to detect the penumbra.
Stroke can result in complete arterial occlusion which leads to the failure of neuronal electrical activity within seconds and then to the deterioration of the energy state within a few minutes. If this lack of energy lasts for longer than 5-10 minutes, irreversible cell damage occurs. The ‘ penumbra’ following stroke relates to brain tissues where blood flow is reduced enough to cause hypoxia affecting neuronal function but where energy metabolism is preserved preventing rapid cell death. This penumbra tissue has the potential to respond to appropriate treatment and recover normal neuronal function. The penumbra surrounds the core of the infarct where severely ischaemic tissue suffers complete energy failure resulting in irreversible injury. Therefore in order to accurately identify the penumbra following ischaemia, it would be necessary to demonstrate hypoperfused brain tissues that have maintained metabolic and electrical activity.
WO 2008/023176 discloses methods of imaging metabolic function. These methods involve contrast imaging techniques of the “BOLD” type but adapted by use together with an oxygen challenge to provide imaging for the assessment of the metabolic responses of tissue over a period of time.
WO 2011/027165 discloses the use of lactate levels in determining the penumbra.
The present invention is based upon the surprising observation that administering a bolus of oxygen via an oxygen carrier (e.g. an intravenous dose of a PFC or other oxygen carrying liquid) allows the penumbra to be readily and accurately determined using MRI.